Cardiovascular disorders including atheroclerosis and hypertension are prominent complications of diabetes mellitus. We propose that these disorders can be correlated with metabolic disorders of hyperlipidemia and accelerated ketogenesis, which in turn are attributable to abnormal Ca2+ functions. In the present proposal, our broad objective is to establish that abnormality of regulatory function of Ca2+ constitutes a link between altered lipid metabolism and smooth muscle pharmacology in the diabetic state. Our specific aims are to: 1) provide further insight into the role of Ca2+ in the ketogenic capacity of hepatocytes from diabetic rats; 2) elucidate the site at which Ca2+ and Ca2+ antagonists (verapamil, TMB-8, nifedipine, etc.) modify the ketogenic pathway; and 3) examine effects of Ca2+ antagonists on in vivo ketosis. Moreover since formation of atheromas and autonomic neurpathy result from Ca2+ dependent alteration of lipid metabolism, we propose to correlated these disorders with changes in vascular muscarinic receptor activities. Two approaches will be used to achieve these objectives. Firstly, diabetes induced lipid disorders will be studied with isolated hepatocytes from control and diabetic rats incubated with 1-14C oleate in the presence and absence of Ca2+ and Ca2+ antagonists. Secondly, classical techniques of receptor pharmacology will be employed to examine diabetes-induced autonomic neuropathy by comparing changes in muscarinic receptors of vascular smooth muscles which are noninnervated with those of the innervated longitudinal smooth muscles of guinea-pig ileum. Also diabetes induced changes in the movement of Ca2+ at the tissue level (hepatocytes and smooth muscle) and organelle level (mitochondria and microsomes) will be examined. The streptozotocin-induced diabetes in rats and guinea-pigs will be the experimental model for the investigation. The results from this investigation will provide the lines of necessary for: 1) locating the sites at which the alteration of Ca2+ metabolism lead to accelerated ketogenesis and the effect Ca2+ -antagonist have on ketogenesis; 2) establishing how the vasculature changes observed in diabetes mellitus correlate with changes in lipid metabolism and ketogenesis and; 3) demonstrating if the observed vascular changes can be detected at the receptor level.